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rifampin; rifampicin (Rifadin, Rimactane)

Tradename: Rifadin, Rimactane. Indications: - treatment of tuberculosis in combination with other agents, especially isoniazid, pyrazinamide & ethambutol - prophylaxis for meningiococcal meningitis (post-exposure) - adjunctive agent for treatment of Staphylococcal infection - including MRSA & coagulase-negative Staphylococci - patients with indwelling foreign bodies [6] - prophylaxis of Haemophilus influenzae type B - adjunctive agent for treatment of - osteomyelitis - anthrax - cutaneous anthrax - inhalation anthrax - leprosy - brucellosis Contraindications: (& cautions) 1) MUST be in conjunction with a bactericidal agent in the treatment of Staphylococcal infection due to the rapid emergence of resistance [6] 2) NOT effective for Staphyloccal urinary tract infections 3) diminishes effectiveness of oral contraceptives: use backup method of contraception to prevent pregnancy 4) use with caution or not at all with antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors [6] 5) coadministration of ritonavir or saquinavir Dosage: 1) tuberculosis: 10-20 mg/kg up to 600 mg PO/IV QD 2) 600 mg PO QD as adjunctive agent for treatment of Staphylococcus infection 3) 600 mg PO BID for 4 days for meningiococcal exposure & Haemophilus influenzae exposure Tabs: 150 & 300 mg. Powder for injection: 600 mg (contains sulfite). Dosage adjustment in renal failure: creatinine clearance dosage > 50-90 mL/min 600 mg every 24 hours 10-50 mL/min 300-600 mg every 24 hours < 10 mL/min* 300-600 mg every 24 hours * No additional dosing for hemodialysis Pharmacokinetics: 1) well absorbed orally 2) food delays absorption 3) 1st pass hepatic metabolism is saturated with higher doses 4) penetrates well into cells & most tissues 5) penetration through non-inflammed meninges is poor, but good CSF concentrations are obtained through inflammed meninges 6) peak serum concentrations 1.5-2 hours after oral ingestion 7) serum levels of 6-7 ug/mL with usual dose 8) MIC of 0.5 ug/mL for most strains of M. tuberculosis 9) eliminated by deacetylation in the liver -> metabolite desacetylrifampin is less active than parent compound 10) 12-15% excreted in the urine, thus minimally effective for urinary tract infections (Staphylococcus) 11) elimination 1/2life is 3 hours (3-11 hours ESRD) a) shorter after the 1st few days of therapy b) increases with increasing dosage & decreases with chronic administration Monitor: - liver function tests (serum AST, serum ALT, serum bilirubin) baseline & at 6 & 12 weeks all patients - in patients with symptoms of liver dysfunction, check serum ALT & serum AST every 2-4 weeks [8,10] Antimicrobial activity: Gram positive - Streptococcus - Streptococcus group A - Streptococcus group B - Streptococcus group C - Streptococcus group G - Streptococcus pneumonia - Enterococcus faecalis (+/-) - Staphylococcus aureus (MSSA, MRSA) - Staphylococcus epidermidis Gram negative - Neisseria gonorrhoeae - Moraxella catarrhalis - Haemophilus influenzae - Francisella tularensis - Brucella species Atypical bacteria - Chlamydia species - Mycobacterium tuberculosis Adverse effects: 1) not common (1-10%) - diarrhea - epigastric cramps - discoloration of urine, feces, saliva, sputum, sweat & tears (reddish orange)* - fungal overgrowth 2) uncommon (< 1%) - drowsiness, fatigue, ataxia, confusion, fever, headache, rash, pruritus, nausea/vomiting, stomatitis, eosinophilia, blood dyscrasias, leukopenia, thrombocytopenia, hepatitis, irritation at site of IV injection, renal failure, flu-like syndrome 3) other - GI upset (most common): nausea/vomiting - skin eruptions - cholestatic jaundice (rare) - acute renal failure at doses > 10 mg/kg - interstitial nephritis - minimal change glomerulonephropathy [6] * Rifampin is excreted in the urine, tears, sweat & other body fluids coloring them orange. Permanent discoloration of soft contact lenses may occur. Drug interactions: 1) rifampin induces cyt P450s CYP1A2, CYP2C9 & CYP3A4 decreasing levels of: - methadone, warfarin, glucocorticoids, estrogens*, digoxin, oral hypoglycemic agents, digitoxin, quinidine, verapamil, mexiletine, theophylline, anticonvulsants, ketoconazole, cyclosporine, barbiturates, chloramphenicol 2) halothane 3) benzodiazepines 4) beta-blockers 5) isoniazid in combination increases hepatotoxicity 6) pyrazinamide in combination may increase hepatotoxicity [9] 7) rifampin decreases serum levels of: a) atovaquone b) saquinavir 8) others -> opiates, verapamil, clofibrate, progestins, disopyramide, probenecid, dapsone 9) use with caution or not at all with antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors [6] - do not use in combination with rilpivirine or etravirine [12] - do not use in combination with ritonavir or saquinavir [6] * diminishes effectiveness of oral contraceptives Laboratory: 1) specimen: a) serum, plasma (heparin, EDTA) b) stable for 3 months at -20 degrees C 2) methods: MB, HPLC Mechanism of action: 1) inhibits DNA-dependent RNA polymerase of mycobacteria & other microorganisms 2) bactericidal for M. tuberculosis

Interactions

drug interactions

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

alcohol alkene; olefin amide amine ester ether heterocyclic compound, 4 or more rings heterocyclic compound, bridged-ring ketone phenol prokaryote-specific molecule rifamycin (rifamycin SV, Rifocin, Aemcolo)

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 2.6-5.1 HOURS protein-binding 75-90% elimination by hemodialysis - peritoneal dialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Sanford Guide to antimicrobial therapy 1997
  3. Am Thoracic Soc, Am J Respir Crit Care Med 149:1359, 1994
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17. American College of Physicians, Philadelphia 1998, 2012, 2015.
  7. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  8. Prescriber's Letter 8(8):48, 2001
  9. Journal Watch 21(19):155, 2001 MMWR Morb Mort Wkly Rep 50:733, 2001
  10. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  11. Deprecated Reference
  12. Centers for Disease Control and Prevention (CDC) Announcement: Updated guidelines on managing drug interactions in the treatment of HIV-related tuberculosis. Morb Mortal Wkly Rep MMWR 2014 Mar 28; 63:272. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6312a5.htm - Centers for Disease Control and Prevention (CDC). Managing drug interactions in the treatment of HIV-related tuberculosis. June 2013. http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/pdf/tbhiv.pdf

Component-of

isoniazid/pyrazinamide/rifampin (Rifater) isoniazid/rifampin (Rifamate)